DESCRIPTION: Studies on the genes involved in inner ear development during embryogenesis should increase our understanding of human inner ear defects resulting in deafness and/or impairment of vestibular function. Although teleosts have a much reduced portion of the inner ear devoted to auditory sensing, the vestibular portion of the inner ear is remarkably similar to that of mammals. Furthermore, the structure of the sensory epithelium in the structures involved in hearing, although present in a much more restricted region of the teleost inner ear, is also conserved in fish and mammals. The zebrafish embryo offers a number of advantages in the identification of genes that may be involved in inner ear defects, and in the experimental testing of the function of genes known to be expressed during the development of the inner ear. The specific aims of this proposal are: (A) To determine the fate map of the inner ear of the zebra fish embryo. Experiments are designed to determine the cells in the gastrula that are fated to become otic placode and otic vesicle, and to trace the ultimate fate in the inner ear of individual cells in the otic vesicle. (B) To genetically identify sets of genes involved in the formation and proper development of the inner ear by carrying out a mutant screen in the zebrafish. In situ hybridization, utilizing probes for genes expressed in particular otic vesicle regions will enable us to rapidly screen the progeny of test crosses for defects in inner ear development. (C) To test for function of genes known to be expressed in the otic vesicle, especially the homeobox gene zOtxl, by investigating the effects of ectopic expression and over-expression of the gene products, and by utilizing a number of approaches to obtain a loss of function of the gene products. This project should increase our knowledge of the early events in formation of the otic vesicle and of its development into specialized structures. The genes identified in this project, and the mechanisms of gene control of otic vesicle development should be relevant to problems of inner ear development in higher vertebrates including humans.